Heparan sulfate (HS) is a ubiquitous component of the cell surface and extracellular matrix. It regulates a wide range of physiologic and pathophysiologic functions, including embryonic development and blood coagulation, and can facilitate viral infection (Esko and Selleck (2002) Annu. Rev. Biochem. 71, 435-471; Liu and Thorp (2002) Med. Res. Rev. 22, 1-25). HS exerts its biological effects by interacting with the specific proteins involved in a given process (Capila and Lindhardt (2002) Angew. Chem. Int Ed. 41, 390-412). HS is a highly charged polysaccharide comprising 1→4-linked glucosamine and glucuronic/iduronic acid units that contain both N- and O-sulfo groups. Unique saccharide sequences within HS can determine the specificity of the binding of HS to its target proteins (Linhardt (2003) J. Med. Chem. 46, 2551-2564). Heparin, a specialized form of HS, is a commonly used anticoagulant drug. Thus, new methods for the synthesis of heparin compounds and HS attract considerable interest for those developing anticoagulant and other HS-related drugs having improved pharmacological effects.
Heparin has been successfully used as an anticoagulant drug for over 50 years (Mackman, 2008). It is currently marketed in three forms: unfractionated (UF) heparin (MWavg ˜14000 Da); a low molecular weight heparin (MWavg ˜6000 Da); and the synthetic ULMW heparin pentasaccharide ARIXTRA® (MW 1508.3 Da). UF heparin is used in surgery and kidney dialysis due to its relatively short half-life and its safety for renal impaired patients (Hirsh et al., 2007). LMW heparins and the ULMW heparin ARIXTRA®, introduced over a decade ago, have played an increasingly important role for preventing venous thrombosis among high risk patients (Tohu et al, 2004; Weitz, 2010) because of their more predictable anticoagulant dose, long half-lives and their reduced risk of osteoporosis (Weitz and Linkins, 2007). Recent research on LMW heparin has resulted in the European approval of Bemiparin sodium (Martinez-Gonzalez and Rodriguez, 2010), a second-generation LMW heparin, and the United States approval of a generic LMW heparin, M-Enoxaparin.
UF heparin is isolated from porcine intestine or bovine lung, and LMW heparins are prepared through the chemical or enzymatic degradation of this animal-sourced UF heparin. A worldwide outbreak of contaminated heparin has raised concerns over the reliability and safety of animal sourced heparins and LMW heparins (Guerrini et al., 2008; Liu et al., 2009). As a result, a cost-effective method for preparing new synthetic heparins is highly desirable (Peterson et al., 2009).